ABSTRACT: Numerous clinical trials failed to modify progression of Alzheimer's Disease (AD) highlighting our incomplete knowledge of the underlying molecular mechanisms. Increasing evidence suggests that AD is a metabolic dis- order with perturbations in pathways essential for cellular energetics occurring early in the disease process: changes in glucose utilization in the brain, a hallmark of AD, correlate well with early clinical disease manifestation; the APOE 4 allele, the strongest genetic risk factor for sporadic AD, is known to affect lipid and cholesterol metabolism; over twenty additional genes linked to AD are implicated in cellular metabolism. Sex has also been demonstrated to play a major role in risk, pathogenesis, progression, and clinical manifestations of AD: women with AD tend to exhibit a broader spectrum of dementia-related behavior and experience greater cognitive deterioration compared to men; female brains are more predisposed to develop AD, and APOE 4, among other genetic risk factors, confers stronger risk in women compared to men. The identification of the key metabolic alterations and pathways underlying differential progression of AD in males vs. females could aid the development of efficacious and disease-modifying therapeutic strategies for AD. The AD Metabolomics Consortium (ADMC) led by one of the PIs in partnership with the AD Neuroimaging Initiative (ADNI) has embarked on mapping metabolic changes in the periphery and in the central nervous system (CNS) across the trajectory of the disease, placing them within a pathway and network context. Our preliminary data demonstrated that among multiple metabolic alterations in blood, changes in lipid metabolism were most prominent in females with AD while changes in branched-chain amino acids (BCAAs) were prevalent in AD males. Predictive networks accompanied by correlations with CSF and imaging biomarkers identified lipids as important drivers of disease in women while BCAAs were marked as drivers in men. Moreover, studies in healthy cohorts in Europe led by one of the PIs demonstrated that women have much higher levels of lipids in blood, while men show significantly higher blood levels of most amino acids, including BCAAs. Based on these observations, we propose the hypothesis that early changes associated with alternative substrate utilization to compensate for altered brain glucose metabolism discriminate mechanistic pathways involved in the disease progression in males vs. females. To test this hypothesis, we assembled a team of investigators with complementary expertise in systems biology, statistics, network analysis, cellular energetics, and animal models to define sex-specific differences in the etiology of AD on a metabolic level. Our team, that has been working collaboratively over the past several years, brings the power of the large, deeply phenotyped ADNI cohorts, state of the art methods in metabolomics, metabolic network reconstruction, imaging and CSF biomarker analysis, and translational studies in animal models to further define molecular mechanisms of disease in men and women with AD in order to develop and test novel therapeutic strategies.